Method and system for producing sterile solution product bags

ABSTRACT

A method for producing sterile solution product bags includes positioning a manifold assembly onto a filling machine. The manifold assembly includes a plurality of bags, a first filter, and a connection line in fluid communication with the first filter. Each of the plurality of bags includes a bladder and a stem in fluid communication with the bladder and with the connection line. The method includes activating a pump and at least partially filling one or more of the bladders by pumping fluid through the feed line, the first filter, and the connection line. The method includes sealing the stem of each of the filled product bags at a location between the connection line and the bladder, thereby creating one or more at least partially filled and sealed product bags. The method includes separating each of the at least partially filled and sealed product bags from the connection line.

FIELD OF DISCLOSURE

The present disclosure relates to sterile solution product bags, andmore particularly, to a method, system, and machine for producingsterile solution product bags.

BACKGROUND

Conventional methods for manufacturing bags of sterile solution includefilling bags in a clean environment with a solution, sealing the filledbag of solution, and then sterilizing the fluid and bags such as in asterilizing autoclave. This can be referred to as terminalsterilization. Another conventional method is to sterile filter asolution and to fill and seal sterile bags in an extremely high-qualityenvironment designed and controlled to prevent contamination of thesolution during the filling process and to seal the filled bag. This canbe referred to as an aseptic filling process.

The terminal sterilization process generally requires one or moreautoclaves to produce the sterilizing heat and steam needed to suitablysterilize the bag of solution for medical use. These autoclavesgenerally are not economical unless they can produce large batches ofterminally sterilized bags. Typically, centralized manufacturingfacilities can afford the capital expenditure needed and spacerequirements to produce and ship the filled bags. In addition to thesecosts, the application of terminal sterilization processes may degradethe solution formulation contained in the bags, thereby leading toincompatible or unstable formulations. Moreover, terminal sterilizationdoes not eliminate non-viable contamination.

The aseptic manufacturing process must occur in a sterile workingenvironment, and requires expensive equipment, stringent procedures andextensive monitoring to ensure that solution product bags meet certainenvironmental and manufacturing regulatory standards. Sterilizing aworking environment, by itself, can be costly and time consuming.Additional precautions apply for technicians involved in the fillingprocess to ensure the production of safe and sterile products. Even withthese safeguards, unless it can be verified that the solution enteringthe bag is sterile, there is a risk that contaminants may haveinadvertently been introduced into the solution during filling/sealing.Once introduced, unless the solution later passes through a viablesterilizing filter, the contaminants will remain in the solution.

SUMMARY

In accordance with a first exemplary aspect, a method for producingsterile solution product bags may include positioning a manifoldassembly onto a filling machine. The manifold assembly may include aplurality of bags, a first filter, and a connection line in fluidcommunication with the first filter. Each of the plurality of bags mayinclude a bladder and a stem having a first end in fluid communicationwith the bladder and a second end in fluid communication with theconnection line. The method may include fluidly coupling a nozzle to theconnection line of the manifold assembly. The nozzle may be in fluidcommunication with a second filter via a feed line. The second filtermay be disposed upstream from the first filter. Further, the method mayinclude activating a pump operatively coupled to the feed line. The pumpmay be disposed upstream from the second filter. The method may includeat least partially filling one or more of the bladders associated withthe plurality of bags by pumping fluid through the feed line, secondfilter, the nozzle, the first filter, and the connection line, therebycreating one or more at least partially filled product bags. The methodmay also include sealing the stem of each of the at least partiallyfilled product bags at a location between the connection line and thebladders of the at least partially filled product bags, thereby creatingone or more at least partially filled and sealed product bags. Finally,the method may include separating each of the at least partially filledand sealed product bags from the connection line.

In accordance with a second exemplary aspect, a system for fillingsterile solution product bags may include a clean chamber, a supportwall disposed above the clean chamber, and a batch filter connected to afeed line. The feed line may be at least partially disposed in the cleanchamber. Further, the system may include a nozzle coupled to an end ofthe feed line and disposed in the clean chamber and a manifold assemblyremovably coupled to the support wall. The manifold assembly may includea plurality of product bags, a connection line, and a manifold filter.Each product bag may include a bladder and a stem connected to thebladder. The connection line may be in fluid communication with thestems of the plurality of the product bags. The manifold filter may havean inlet and an outlet. The inlet may be operatively coupled to thenozzle and the outlet may be operatively coupled to the connection line.A pump may be coupled to the feed line and configured to pump a fluidthrough the batch filter, the feed line, the nozzle, the manifoldfilter, the connection line, and into each of the plurality of productbags.

In accordance with a third exemplary aspect, a system for producingsterile solution product bags may include a mix bag (or mix tank) formixing a solution and a filling machine adapted to receive the solutionfrom the mix bag for filling an empty bag set. The filling machine mayinclude a clean chamber. a support wall disposed above the clean chamberand a batch filter connected to a feed line. The feed line may be atleast partially disposed in the clean chamber. The filling machine mayinclude a nozzle formed at an end of the feed line and disposed in theclean chamber and a manifold assembly removably coupled to the supportwall. The manifold assembly may include a plurality of product bags.Each product bag may include a bladder and a stem connected to thebladder. A connection line may be in fluid communication with the stemsof the plurality of the product bags. A manifold filter may have aninlet and an outlet. The inlet may be operatively coupled to the nozzleand the outlet may be operatively coupled to the connection line. A pumpmay be coupled to the feed line and may be configured to pump a fluidthrough the batch filter, the feed line, the nozzle, the manifoldfilter, the connection line, and into each of the plurality of productbags. A filter integrity test machine may be configured to perform atleast one of a bubble point test and a pressure degradation test on thefirst filter.

In accordance with a fourth exemplary aspect, a method for producingsterile solution product bags may include positioning a manifoldassembly onto a filling machine. The manifold assembly may include aplurality of bags, a first filter, and a connection line in fluidcommunication with the first filter. Each of the plurality of bags mayinclude a bladder and a stem having a first end in fluid communicationwith the bladder and a second end in fluid communication with theconnection line. The method may further include coupling a nozzle to theconnection line of the manifold assembly. The nozzle may be in fluidcommunication with a second filter via a feed line. The second filtermay be disposed upstream from the first filter. The method may includeactivating a pump operatively coupled to the feed line. The pump may bedisposed upstream from the second filter. Further, the method mayinclude at least partially filling one or more of the bladdersassociated with the plurality of bags with] headspace by pumping fluidthrough the feed line, second filter, the nozzle, the first filter, andthe connection line, thereby creating one or more at least partiallyfilled product bags. The method may then include sealing the stem ofeach of the at least partially filled product bags at a location betweenthe connection line and the bladders of the at least partially filledproduct bags, thereby creating one or more at least partially filled andsealed product bags. Finally, the method may include separating each ofthe at least partially filled and sealed product bags from theconnection line.

In accordance with a fifth exemplary aspect, a method for producingsterile solution product bags may include positioning a manifoldassembly onto a filling machine. The manifold assembly may include aplurality of bags, a first filter, and a connection line in fluidcommunication with the first filter. Each of the plurality of bags mayinclude a bladder and a stem having a first end in fluid communicationwith the bladder and a second end in fluid communication with theconnection line. The method may include coupling a nozzle to theconnection line of the manifold assembly. The nozzle may be in fluidcommunication with a second filter disposed upstream from the firstfilter. The method may further include at least partially filling one ormore of the bladders associated with the plurality of bags by pumpingfluid through the second filter, the nozzle, the first filter, and theconnection line, thereby creating one or more partially filled productbags. The method may include sealing the stem of each at least partiallyfilled product bags at a location between the connection line and thebladder of the at least partially filled product bags, thereby creatingone or more at least partially filled and sealed product bags having aseal. Finally, the method may include separating, at the seal, each ofthe at least partially filled and sealed product bags from theconnection line.

In accordance with a sixth exemplary aspect, a method of finalizingsterile solution product bags may include providing a manifold assemblyhaving a plurality of partially filled bags and a connection line influid communication with an outlet of the filter. The plurality ofpartially filled bags may be connected to a filter, and each of thepartially filled bags may include a partially filled bladder and a stemhaving a first end in fluid communication with the partially filledbladder and a second end in fluid communication with the connectionline. The method may include sealing the stem associated with each ofthe partially filled bags at a first location between the partiallyfilled bladder and the connection line, thereby creating one or morepartially filled and sealed product bags. The method may includeseparating each stem of the at least partially filled and sealed productbags from the connection line. The method may include sealing theconnection line at a second location adjacent to the outlet of thefilter. Finally, the method may include separating the filter from theconnection line.

In accordance with a seventh exemplary aspect, a system for finalizingsterile solution product bags may include a sealing tool movable betweenan open position and a clamped position. The sealing tool may have ahand grip, a lever, and a clamp coupled to the lever. The hand grip mayhave a distal end proximate to the clamp that emits RF energy. A cuttingtool may be movable between an open position and a closed position. Thecutting tool may include a hand grip, a lever, a blade coupled to thehand grip, and a stop coupled to the lever. The stop may be sized toreceive the blade when the cutting tool is in the closed position. Thestop may be spaced away from the blade when the cutting tool is in theopen position.

In accordance with a eighth exemplary aspect, a system for finalizingsterile solution product bags may include a sealing means having asealing element formed in opposing clamped surfaces that are configuredto collapse and at least partially melt and sealing fuse the innerpassageway, and a lever. The lever may be movable between an openposition, in which the element is deactivated, and a clamped position,in which the element is activated and applies a radiofrequency energybetween the opposing clamped surfaces. A cutting means may include ablade and a stop. The blade may be movable between an open position, inwhich the blade is spaced from the stop, and a closed position, in whichthe blade engages the stop.

In accordance with a ninth exemplary aspect, a method for producingsterile solution product bags may include positioning a manifoldassembly onto a filling machine. The manifold assembly may include aproduct bag, a first filter, and a connection line in fluidcommunication with the first filter. The product bag may be mounted to asupport wall of the filling machine. The method may include coupling anozzle to the connection line of the manifold assembly in a cleanchamber of the filling machine. The nozzle may be disposed in a nozzleholder and in fluid communication with a second filter via a feed line.The second filter may be disposed upstream from the first filter, andthe clean chamber may be disposed below the support wall of the fillingmachine. The method may include activating a pump operatively coupled tothe feed line. The pump may be disposed upstream from the second filter.Further, the method may include at least partially filling a bladder ofthe product bag by pumping fluid through the feed line, second filter,the nozzle, the first filter, and the connection line, thereby creatingan at least partially filled product bag. The method may include sealingthe stem of the at least partially filled product bag at a locationbetween the connection line and the bladder of the at least partiallyfilled product bag, thereby creating an at least partially filled andsealed product bag. Finally, the method may include separating the atleast partially filled and sealed product bag from the connection line.

In accordance with a tenth exemplary aspect, a system for fillingsterile solution product bags may include a clean chamber, a batchfilter connected to a feed line, where the feed line is at leastpartially disposed in the clean chamber, a nozzle coupled to an end ofthe feed line, and a filling connection assembly disposed in the cleanchamber. The assembly may include a first actuator carrying the nozzle,a second actuator carrying a cutting tool. A manifold filter may be atleast partially disposed in the clean chamber and may have an inletoperatively coupled to the nozzle. A pump may be coupled to the feedline and configured to pump a fluid through the batch filter, the feedline, the nozzle, and the manifold filter.

In accordance with an eleventh exemplary aspect, a filling connectionassembly for a filling machine may include a nozzle holder movablebetween an extended position and a retracted position. A first actuatormay carry the nozzle holder and may be movable along a first axis. Acutting tool may have a blade and may be movable between an extendedposition and a retracted position. A second actuator may carry thecutting tool and may be movable along a second axis perpendicular to thefirst axis. A line grip may be movable between an extended position anda retracted position. A third actuator may carry the line grip and maybe movable along a third axis perpendicular to the first axis. A cleanchamber may house the nozzle holder, the first actuator, the cuttingtool, the second actuator, the line grip, and the third actuator.

In further accordance with any one or more of the foregoing firstthrough eleventh aspects, a method and system for producing sterilesolution product bags, a method and system for filling sterile solutionproduct bags, a method and system of finalizing sterile solution productbags, and a filling connection assembly for a filling machine mayfurther include any one or more of the following preferred forms.

In a preferred form, the method may include performing a filterintegrity test on the first filter.

In a preferred form, at least partially filling one or more of thebladders associated with the plurality of bags may include filling afirst bag before filling a second bag.

In a preferred form, the method may include activating a occlusion valvedisposed adjacent to the stem of one product bag of the plurality ofproduct bags and movable between a compressed position, in which theocclusion valve compresses the stem of the one product bag preventingfluid from flowing through the stem and into the bladder of the oneproduct bag, and an extended position, in which the occlusion valvereleases the stem of the one product bag permitting fluid to flowthrough the stem and into the bladder of the one product bag.

In a preferred form, controlling fluid flow may include activating oneof a plurality of occlusion valves.

In a preferred form, each of the plurality of occlusion valves may beadjacent to one product bag of the plurality of product bags.

In a preferred form, the method may include deactivating the occlusionvalve to move the occlusion valve from the extended position to thecompressed position after the one product bag is filled with apredetermined amount of fluid.

In a preferred form, at least partially filling one or more of thebladders associated with the plurality of bags may include filling afirst product bag when a first occlusion valve is in the extendedposition and a second occlusion valve is in the compressed position.

In a preferred form, the first occlusion valve may be adjacent to thefirst product bag and the second occlusion valve may be adjacent to asecond product bag.

In a preferred form, at least partially filling one or more of thebladders associated with the plurality of bags may include filling thesecond product bag when the second occlusion valve is in the extendedposition and the first occlusion valve is in the compressed position.

In a preferred form, at least partially filling one or more of thebladders associated with the plurality of bags may include priming afirst bag set by filling bladders of the first bag set with fluid anddistributing air from the second filter into the first bag set.

In a preferred form, at least partially filling one or more of thebladders associated with the plurality of bags may include fillingbladders of a second bag set with fluid and calibrating a plurality ofproduct bags of the second bag set by weighing at least one bag of thesecond bag set and comparing a weight of the at least one bag with apredetermined value.

In a preferred form, at least partially filling one or more of thebladders associated with the plurality of bags may include fillingbladders of a third bag set with fluid and performing a filter integritytest on a first filter connected to the third empty bag set.

In a preferred form, the third bag set may include the plurality ofbags.

In a preferred form, positioning a manifold assembly may be performedbefore at least partially filling one or more of the bladders associatedwith the plurality of bags of the first, second, and third bag sets withfluid.

In a preferred form, positioning a manifold assembly includes suspendingthe bladder of each of the plurality of product bags in a position wherethe stem is below the bladder and the first filter is below theplurality of product bags.

In a preferred form, a plurality of occlusion valves may be operativelycoupled to the support wall.

In a preferred form, each occlusion valve may be disposed adjacent toone product bag of the plurality of product bags and may be movablebetween a compressed position, in which the occlusion valve compressesthe stem of one product bag to prevent fluid from flowing through thestem and into the bladder of the one product bag, and an extendedposition, in which the occlusion valve releases the stem of the oneproduct bag to permit fluid to flow through the stem and into thebladder of the one product bag.

In a preferred form, each occlusion valve may have anelectromechanically actuated solenoid.

In a preferred form, a plurality of clips may be to the support wall.

In a preferred form, each clip being may be coupled to the bladder ofone product bag of the plurality of product bags.

In a preferred form, the connection line may be in fluid communicationwith the stem of each of the plurality of product bags.

In a preferred form, a platform may be between the support wall and theclean chamber.

In a preferred form, the platform may define an opening sized to receivethe manifold filter such that the inlet of the manifold filter isdisposed in the clean chamber.

In a preferred form, a HEPA filter may filter air flowing through theclean chamber.

In a preferred form, the system may include a user interface and acontroller.

In a preferred form, the controller may be programmed to prompt a uservia the user interface to perform a plurality of steps to operate thesystem.

In a preferred form, the system may include a plurality filling machinesin which the mix bag station may be fluidly connected to each of theplurality of filling machines.

In a preferred form, the plurality of filling machines may be arrangedin an efficient configuration, such as a U-shaped configuration.

In a preferred form, the system may include a plurality of filterintegrity test machines.

In a preferred form, the ratio of filling machines and filter integritytest machines may be 1:1.

In a preferred form, the system may include multiple mix bags.

In a preferred form, sealing the stem may include creating the seal byapplying radiofrequency energy to the location of the stem.

In a preferred form, the method may include aligning a cutting tool atthe location between the connection line and each bladder of the atleast partially filled product bags such that a blade of the cuttingtool is aligned with a center point of the seal formed in the stem ofeach of the at least partially filled and sealed product bags from theconnection line.

In a preferred form, separating may include cutting the stem of each atleast partially filled and sealed product bags at the location betweenthe connection line and the bladders, thereby creating a cut in the stemsuch that the stem is sealed at a first side and a second side of thecut.

In a preferred form, sealing the stem may include creating a hot notchedseal.

In a preferred form, separating each of the at least partially filledand sealed product bags may include pulling the stem to tear at the hotnotched seal.

In a preferred form, sealing the stem of each at least partially filledproduct bags may include clamping a sealing tool around the location ofthe stem and applying radiofrequency energy to the location of the stem.

In a preferred form, the method may include activating an alarm when aninadequate seal is formed in the stem.

In a preferred form, the method may include determining an adequacy ofthe seal in which the seal is inadequate when at least one of (a) and(b) is detected, where (a) failing to meet a sealing time threshold, and(b) releasing a sealing tool when the power delivered meets establishedprocess requirements.

In a preferred form, the method may include displaying a firstidentifier to begin sealing and displaying a second identifier to stopsealing.

In a preferred form, the method may include sealing the connection lineat a second location adjacent to an outlet of the filter, therebycreating a second seal.

In a preferred form, the method may include separating, at the secondseal, the filter from the manifold assembly.

In a preferred form, the method may include performing a filterintegrity test on the filter after separating the filter from themanifold assembly.

In a preferred form, sealing the stem of each at least partially filledproduct bags may include sealing a stem associated with the first bagwhile the second bag is being at least partially filled with fluid.

In a preferred form, the method may include aligning a sealing tool atthe location between the connection line and each bladder of the atleast partially filled product bags.

In a preferred form, sealing the stem may include creating a seal byapplying radiofrequency energy to the location of the stem.

In a preferred form, sealing the stem may include creating a hot notchedseal and wherein separating each of the at least partially filled andsealed product bags includes pulling the stem to tear at the hot notchedseal.

In a preferred form, the method may include displaying a firstidentifier to begin sealing and displaying a second identifier to stopsealing.

In a preferred form, a mount may be configured to receive the sealingtool and the cutting tool and align the distal end to a seal locationand to align the blade to the seal location.

In a preferred form, a controller may be communicatively coupled to thesealing tool and a user interface may be communicatively coupled to thecontroller.

In a preferred form, the user interface may be configured to displayinformation sent from the sealing tool to the controller.

In a preferred form, the sealing tool may include a sensor that measuresduration of energy applied by the sealing tool when the sealing tool isin the clamped position.

In a preferred form, the controller may be programmed to prompt a uservia the user interface to perform a plurality of steps to operate thesealing tool and the cutting tool.

In preferred form, the plurality of steps may include clamp a connectionline with the sealing tool and release the clamp from the connectionline.

In a preferred form, the sealing means may be separate from the cuttingmeans.

In a preferred form, a mount may be configured to receive the sealingmeans and the cutting means and align the clamping element of thesealing means to a seal location and to align the blade to the seallocation.

In a preferred form, the sealing means may be integrated with thecutting means.

In a preferred form, the sealing means may include a sensor thatmeasures duration of the sealing means when the clamping element appliesradiofrequency energy.

In a preferred form, the sealing means may be configured to measure animpedance change between the opposing clamped surfaces.

In a preferred form, the sealing means may turn off the emitted energyof the clamping element when a desired impedance change is met.

In further accordance with any one or more of the foregoing first,second, or third aspects, a method for producing sterile solutionproduct bags, a system for filling sterile solution product bags, and afilling connection assembly for a filling machine may further includeany one or more of the following preferred forms.

In a preferred form, coupling the nozzle may include moving the nozzlealong a longitudinal axis of the nozzle.

In a preferred form, the nozzle may be sized to sealably couple to aportion of the of the manifold assembly.

In a preferred form, the method may further include opening a sealed endof a connection tube connected to the first filter before coupling thenozzle to the connection tube.

In a preferred form, the sealed end of the connection tube may bedisposed between the nozzle and an inlet of the first filter.

In a preferred form, opening the sealed end may include cutting theconnection tube at a location between the sealed end and the inlet ofthe first filter, thereby creating an open end of the connection tube.

In a preferred form, opening the sealed end may include holding theconnection tube and moving a cutter, via a side actuator, along a secondaxis toward the connection tube and removing the sealed end from theconnection tube.

In a preferred form, holding the connection tube may include engagingthe connection tube with a line grip.

In a preferred form, the line grip may be movable along a third axis bya second side actuator.

In a preferred form, the method may include placing the nozzle in thenozzle holder that is movable along a first axis between a firstposition and a second position.

In a preferred form, the nozzle holder may be movable by an actuator.

In a preferred form, the method may include removing a cap coupled tothe nozzle before coupling the nozzle to the connection line.

In a preferred form, placing the nozzle may include placing the cap intoa holder situated above the nozzle holder.

In a preferred form, removing the cap may include moving the nozzleholder between the first position and the second position, and engagingthe cap with the holder.

In a preferred form, positioning the manifold assembly may includeplacing the first filter into a compartment disposed between the supportwall and the clean chamber.

In a preferred form, the method may include reversing the pump beforedecoupling the nozzle from the connection line.

In a preferred form, the nozzle may be movable by the first actuatorbetween an extended position and a retracted position relative to afirst axis.

In a preferred form, the cutting tool may be movable by the secondactuator between an extended position and a retracted position relativeto a second axis.

In a preferred form, the second axis may be perpendicular to the firstaxis.

In a preferred form, a gripping tool may be carried by a third actuatorand may be movable between an extended position and a retracted positionrelative to a third axis.

In a preferred form, the third axis may be perpendicular to the firstaxis.

In a preferred form, the gripping tool may include an opening sized toreceive a portion of a connection tube connected to the inlet of themanifold filter.

In a preferred form, the cutting tool may include a blade.

In a preferred form, the gripping tool may include a slot sized toreceive the blade of the cutting tool when the second actuator is in theextended position and the third actuator is in the extended position.

In a preferred form, a platform may be between the support wall and theclean chamber.

In a preferred form, the platform may define an opening sized to receivethe manifold filter.

In a preferred form, a protective door may cover the opening and may berotatable relative to the opening.

In a preferred form, a cap removal tool may be removably disposed withinthe opening.

In a preferred form, the assembly may include a support wall disposedabove the clean chamber and a manifold assembly removably coupled to thesupport wall.

In a preferred form, the manifold assembly may include a plurality ofproduct bags and a connection line in fluid communication with theplurality of the product bags.

In a preferred form, the manifold filter may include an outlet fluidlycoupled to the plurality of bags.

In a preferred form, the line grip may include an opening sized toreceive a connection tube and may rigidly support the connection tubewhen the line grip is in the extended position.

In a preferred form, the line grip may include a slot sized to receivethe blade of the cutting tool when the cutting tool is in the extendedposition.

In a preferred form, the second actuator may carry an angled chutedisposed below the blade of the cutting tool.

In a preferred form, a cap removal tool may be disposed above the nozzleholder.

In a preferred form, the cap removal tool may include a first openingand a second opening orthogonal to the first opening.

In a preferred form, the first and second openings may be differentsizes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a sterile solution product bag fillingmachine assembled in accordance with the teachings of the presentdisclosure;

FIG. 2 is a front view of the machine of FIG. 1 ;

FIG. 3 is a front view of the machine of FIG. 1 with a clean chamberdoor open;

FIG. 4 is a front, magnified view of a first exemplary manifold assemblyattached to the machine of FIG. 1 and with a sealing tool in position;

FIG. 5 is a perspective view of the manifold assembly attached to themachine of FIG. 4 ;

FIG. 6 is a front, magnified view of the machine of FIG. 1 , showing afilter attached to the manifold assembly and a protective door in anopen position and assembled in accordance with the teachings of thepresent disclosure;

FIG. 7 is a front, magnified view of the machine of FIG. 6 , showing theprotective door in a closed position;

FIG. 8 is a cross-sectional view of the filter and the protective doorof FIG. 7 in the closed position;

FIG. 9 is a front view of a second exemplary manifold assembly assembledin accordance with the teachings of the present disclosure;

FIG. 10 is a front view of an exemplary occlusion valve used with themachine of FIG. 1 and assembled in accordance with the teachings of thepresent disclosure;

FIG. 11 is a cross-sectional view of the occlusion valve of FIG. 10taken at A-A;

FIG. 12 is a perspective view of the sealing tool assembled inaccordance with the teachings of the present disclosure;

FIG. 13 is a partial side view of a cutting tool assembled in accordancewith the teachings of the present disclosure;

FIG. 14 is a partial perspective view of the cutting tool of FIG. 13 ;

FIG. 15 is a schematic of an exemplary method of producing sterilesolution product bags;

FIG. 16 is a front view of a connection assembly of the clean chamber ofFIG. 1 in an initial position;

FIG. 17 is a front, magnified view of the connection assembly of FIG. 16;

FIG. 18 is a front view of the connection assembly of the clean chamberof FIG. 1 after a cap of a nozzle is removed;

FIG. 19 is a front view of the connection assembly of the clean chamberof FIG. 1 , showing a connection tube being held in vertical alignmentwith the nozzle;

FIG. 20 is a front view of the connection assembly of the clean chamberof FIG. 1 , showing a cutting tool engaging the connection tube;

FIG. 21 is a front, magnified view of the connection assembly of FIG. 20;

FIG. 22 is a front view of the connection assembly of the clean chamberof FIG. 1 , showing the nozzle engaged with the connection tube;

FIG. 23 is a front, magnified view of the connection assembly of FIG. 22;

FIG. 24 is a partial view of the sealing tool of FIG. 12 aligned with astem of a product bag of the manifold assembly of FIG. 4 ;

FIG. 25 is a magnified view of the sealing tool aligned with the stem ofthe product bag of FIG. 24 ;

FIG. 26 is a cross-sectional, perspective view of the sealing toolaligned with the stem of the product bag of FIG. 24 ;

FIG. 27 is a partial view of the cutting tool of FIGS. 13 and 14 alignedin with the stem of the product bag of the manifold assembly of FIG. 4 ;

FIG. 28 is a magnified view of the cutting tool aligned with the stem ofthe product bag of FIG. 27 ;

FIG. 29 is a cross-sectional view of the cutting tool aligned with thestem of the product bag of FIG. 27 .

FIG. 30 is a top view of a first exemplary schematic of a system forproducing sterile solution product bags assembled in accordance with theteachings of the present disclosure;

FIG. 31 is a top view of a second exemplary schematic of a system forproducing sterile solution product bags assembled in accordance with theteachings of the present disclosure;

FIG. 32 is a top view of a third exemplary schematic of a system forproducing sterile solution product bags assembled in accordance with theteachings of the present disclosure;

FIG. 33 is a perspective view of a bracket for holding a manifoldassembly assembled in accordance with the teachings of the presentdisclosure;

FIG. 34 is a perspective view of a loaded manifold bracket in accordancewith the teachings of the present disclosure;

FIG. 35 is a perspective view of the loaded manifold bracket attached tothe machine of FIG. 3 ;

FIG. 36 is a perspective view of a storage rack holding a plurality ofbrackets with filled product bags assembled in accordance with theteachings of the present disclosure; and

FIGS. 37A and 37B are perspective views of an exemplary system forconducting a filter integrity test in accordance with the teachings ofthe present disclosure.

DETAILED DESCRIPTION

In FIGS. 1-3 , a machine 10 for filling sterile solution product bags isconstructed in accordance with the teachings of the present disclosure.The machine 10 includes a clean chamber 14, a support wall 18 disposedabove the clean chamber 14, and a platform 22 disposed between the cleanchamber 14 and the support wall 18. A user interface 26 is mounted tothe support wall 18 and an on-board central processing unit (CPU) 28 iscommunicatively coupled to the interface 26 and is protected by ahousing 30 of the machine 10. A scale 34, which is in communication withthe CPU 28, is disposed adjacent to the support wall 18 and on top ofthe platform 22. However, in other examples, the scale 34 may be locatedelsewhere relative to the machine 10. The machine 10 is mobile to permitan operator to move the machine 10 easily, however, in other examples,the machine 10 may be semi-permanently or permanently installed orotherwise configured so that the machine 10 may be easily moved to adesired position such as being mounted on wheels.

Some embodiments may be described using the expression “coupled” and“connected” along with their derivatives. For example, some embodimentsmay be described using the term “coupled” to indicate that two or moreelements are in direct physical or electrical contact. The term“coupled,” however, may also mean that two or more elements are not indirect contact with each other, but yet still co-operate or interactwith each other. The embodiments are not limited in this context.

As shown in FIGS. 1-4 , a first exemplary manifold assembly 38 ismounted to the support wall 18 in an upside-down configuration. Themanifold assembly 38 is removably coupled to the support wall 18 by aplurality of hooks (e.g., a spring-forced latch) 42 located at an upperend of the machine housing 30. The manifold assembly 38 includes aplurality of product bags 46, a connection line 50, and a manifoldfilter 54. As described in more detail below, each product bag 46includes a bladder 58 and a stem 62 connected to the bladder 58. Eachstem 62 has a first end 63 in fluid communication with the bladder 58 ofone product bag 46 and a second end 64 in fluid communication with theconnection line 50. The connection line 50 is in fluid communicationwith each of the stems 62 of the plurality of the product bags 46, andis perpendicularly situated relative to each stem 62. The manifoldassembly 38 is a closed system that is pre-sterilized such that thefilter, filter housing, and any fluid contact surface downstream of thefilter is sterile.

Like the manifold assembly 38, the manifold filter 54 is disposed in anupside-down configuration such that an inlet 65 of the manifold filter54 faces downward. The manifold filter 54 includes the inlet 65 and anoutlet 67 where the inlet 65 is operatively coupled to a nozzle 66 of afeed line 70 when the nozzle 66 is coupled to the manifold assembly 38.The outlet 67 of the manifold filter 54 is operatively coupled to theconnection line 50 of the manifold assembly 38 such that all fluidflowing through the connection line 50 has already passed through themanifold filter 54. Preferably, when the manifold filter 54 is coupledto the machine 10, the inlet 65 is disposed in the clean chamber 14 andthe outlet 67 is disposed above the platform 22.

The filter material of the manifold filter 54 may be a fibrous materialdesigned and rated to be a sterilizing grade filter. In one example, thefibrous material may be produced with a porosity of 0.2 microns (μm). Inother examples, the porosity of the fibrous material can vary to addressfiltration requirements. By way of example, the porosity can be lessthan 0.2 microns. Other versions of sterilizing grade filters are alsocontemplated. The filter pore size of the manifold filter 54 effectivelysterilizes the solution and removes non-viable contaminants. By way ofexample, the porous membrane material can be treated such as to impart astatic electrical charge to the membrane in order to further facilitateremoval of viable and non-viable content from the fluid being filtered.The manifold assembly 38 is not limited to the example illustrated inFIGS. 1-4 , but may have a different manifold assembly configurationhaving a filtering capacity and that adequately sterilizes the solutionand removes non-viable contaminants in the solution. Sterilization andcontaminant removal requirements as it relates to filter pore size mayvary according to the fluid being processed.

The clean chamber 14 is enclosed by a slotted door 82 and is shown in aclosed position in FIG. 2 and in an open position in FIG. 3 . Depictedin FIG. 3 , the feed line 70 is coupled to the nozzle 66, is at leastpartially disposed in the clean chamber 14, and extends outside of theclean chamber 14 to connect to a batch filter 86. Also disposed in theclean chamber 14 is the nozzle 66 and a connection assembly 90 includinga nozzle holder 92, a cutting tool 94, and a support tool 98 (alsoreferred herein as a “line grip”). The connection assembly 90 may be anautomated process of the machine 10 to prevent touch contaminationduring the connection of the nozzle 66 to the manifold assembly 38. Theclean chamber 14 is kept “clean” by continuously passing air through aHEPA filter disposed in the back of the clean chamber 14 to form alaminar flow from the rear of the chamber through the slots in theslotted door 82 when in the closed position. A filter train is partiallydepicted in FIG. 3 and includes the feed line 70 and the batch filter86. The feed line 70 extends from the batch filter 86 and makes asterile connection at a valve port with a mix tank.

“Clean” or “clean air,” in the context of cleanroom environments, forexample can be defined by one of two standards used to test andcategorize the class of air. These two standards include the UnitedStates Federal Standard 209E and the International Standard ISO 14644-1.Both standards define terms, identify procedures for collecting andtesting the air, and provide the statistical analysis required tointerpret the data. Federal Standard 209E classifications of air includeClass 1, Class 10, Class 100, Class 1,000, Class 10,000, and Class100,000. The class number (e.g., 100) is the maximum allowable number ofparticles 0.5 microns and larger per cubic foot of air; the lower thenumber, the cleaner the air. The ISO classifications are rated as ISOClass 1, ISO Class 2, ISO Class 3, etc. through ISO Class 9. Class 1under both standards indicates the cleanest, ultrapure air. The ISOClass 2 correlates most closely to Federal Standard Class 100.Therefore, in accordance with the present application, “clean” or “cleanair” can include, for example, any air classified in the range ofclasses from class 100 to class 100,000 under US Federal Standard 209Eand, in one embodiment, in the range of classes from class 10,000 toclass 100,000 under US Federal Standard 209E or Grade A under Europeanclassification system of “Grade” air.

Below the clean chamber 14, a pump 102, such as a peristaltic pump, iscoupled to the feed line 70 of the filter train and is configured toselectively pump a solution from a mix tank through the batch filter 86,the feed line 70, the nozzle 66, the manifold filter 54, the connectionline 50, and into each of the plurality of product bags 46. Also belowthe chamber 14, a receptacle 106 is attached to the machine 10 and ispositioned to collect any waste from the clean chamber 14 (such assolution leaked at the nozzle 66 or manifold filter 54). As referredherein, the term “solution” is a fluid, such as saline and/or any typeof fluid medicinal product. The solution, in this example, is mixed in amix bag or tank, which may be sterile and single-use, in the samefacility, and in some cases, the same room as the filling machine 10.The solution may be mixed in a system such as the mix bag systemdisclosed in U.S. patent application Ser. No. 16/392,074 filed Apr. 23,2019, the contents of which are incorporated entirely by reference. Thesolution may also be mixed in a pharmaceutical solution mixing vesselfound in many pharmaceutical solution production facilities. Forexample, the mix tank may have a disposable container or may have animpeller to mix the solution. In some examples, the mix tank may be astainless steel pharmaceutical grade mix tank.

In FIG. 4 , the support wall 18 and the first exemplary manifoldassembly 38 are more clearly illustrated. The manifold assembly 38includes six product bags 46 a, 46 b, 46 c, 46 d, 46 e, 46 f where eachproduct bag 46 is attached to the support wall 18 by the spring-forcelatch 42, or in other examples, a different hook, mounting pin, or otherremovable fastener. Each product bag 46 includes the bladder 58, thestem 62, and a sealed or plugged administration or medication port 108.The bladder 58 is a fillable pouch that can have a standard volumecapacity with an interior that is pre-sterilized. At least partiallysurrounding a perimeter of the fillable pouch is a sealed border 112having an aperture 116 configured to receive the spring-force latch 42,hook, or mounting pin for mounting the bag 46 to the support wall 18 ofthe machine 10. In particular, the aperture 116 is formed at a first end118 of the product bag 46, and the bladder 58 is fluidly connected tothe stem 62 at an opening at a second end 120 of the bladder 58. Whilethe illustrated manifold assembly 38 includes six product bags, otherexemplary manifold assemblies 38 may have more or fewer than six productbags.

The CPU 28 may be programmed to store data for each batch of viableproduct bags 46 that have been filled and tested for sterility. Beforefilling, an operator may enter a serial number associated with themanifold assembly 38 into the CPU 28 via the user interface 26 to storetype of solution, solution expiration, filling date and location, fluidconductivity and integrity results, and other information pertainingproduct bags 46. In other examples, each batch of filled product bags 46may be serialized with a barcode, QR code, RFID tag or other identifierto identify critical information related to the filled bag 46 with orwithout the use of the CPU 28.

The manifold assembly 38 is positioned above the nozzle 66 so that thepump 102 works against gravity to fill each product bag 46. Theconnection line 50, which is disposed below the plurality of bags 46, isin fluid communication with the inlet of each bladder 58 of theplurality of product bags 46 via the stem 62. The connection line 50 isconnected to the stems 62 of each product bag 46, and each stem 62 isclamped in vertical alignment to the support wall 18 by a wall clamp ora occlusion valve 134. Above the occlusion valves 134 and below eachproduct bag 46, a plurality of shelving units 136 protrude from thesupport wall 18 to provide a stable mount for each of the sealing andcutting tools 138, 174. For example, in FIGS. 1-4 a sealing tool 138 isplaced below the sixth bag 46 f (in FIG. 4 ) and rests on the shelvingunit 136 below the bag 46 f.

In FIG. 4 , a plurality of occlusion valves 134 are arranged to coupleto the stems 62 of the plurality of product bags 46. Each occlusionvalve 134 is movable between a compressed position and an extendedposition to, respectively, prevent and allow air and/or fluid to flowthrough the stem 62 and into the product bag 46. In the compressedposition, the occlusion valve 134 compresses the stem 62 of theassociated product bag 46 to prevent air and/or fluid from flowingthrough the stem 46 and into the bladder 58. In the extended position,the occlusion valve 134 releases the compression of the stem 62 of theassociated product bag 46 and permits air and/or fluid to flow throughthe stem 62 and into the bladder 58 of the associated product bag 46.When one occlusion valve 134 is in the extended position, fluid and/orair may flow into the associated product bag 46 and the remainingocclusion valves 134 are in compressed positions. This ensures that onlyone product bag 46 is filled at a time and in particular order. Afterthe filling process for a given bag 46 is complete, each of theocclusion valves 134 returns to the compressed position.

Shown in greater detail in FIG. 5 , the sealing tool 138 is coupled toone of the plurality of shelving units 136 of the machine 10. Each ofthe plurality of shelving units 136 includes a protruding platform 140and a stem grip 142 disposed over the platform 140 and configured togrip a portion of the second end 120 of the product bag 46. The stemgrip 142 extends downward towards the platform 140 and provides a notch144 that is sized to receive and accurately register a head (alsoreferred herein as a “clamp” of the sealing tool and a “stop” of thecutting tool 174) of both the sealing tool 138 and a cutting tool 174.When resting on the platform 140 and snapped into the notch 144 of theshelving unit 136, the sealing tool 138 is in position to make a wideseal without relying on the placement accuracy of an operator. Theoperator need only slide the sealing tool 138 onto the platform 140toward the support wall 18, slide the head or clamp of the sealing tool138 toward the stem 62 and into a registration position within the notch144, and activate the sealing tool 138 to make an accurately positionedseal. Activating the sealing tool 138 may include, for example, emittingradiofrequency (RF) energy into the material of the stem 62 to seal. Theconfiguration of the platform 140 and notch 144 of the shelving unit 136is shaped and sized to receive and register a cutting tool 174 in thesame or similar way as the sealing tool 138 to ensure that the cuttingtool 174 is in proper alignment with the wide seal made by the sealingtool 138. When placed on the platform 140 and snapped into the notch144, the cutting tool 174 is in place to make an accurately positionedcut to separate the sealed and filled product bag 46 from the connectionline 50. The connection line 50 and the stem 62 attached to the productbag 46 are both sealed because of the wide seal and cut centeredrelative to the seal.

In FIGS. 1 and 6-8 , the platform 22 is clearly illustrated. In additionto providing a table-top surface for temporarily placing items not yetin use (e.g., the manifold assembly 38, a sealing tool 138, a cuttingtool 174) when operating the machine 10, the platform 22 includes anopening 74 in which the manifold filter 54 is removably disposed. Theopening 74 is protected by a hinged, protective door 78 that swings toan open position, as shown in FIG. 6 , to access the manifold filter 54,and a closed position, as shown in FIGS. 7 and 8 , to register themanifold filter 54 and, in a preferred embodiment, protect the cleanchamber 14 from the surrounding environment. The hinged door 78 includesa notch 79 sized so that the door 78 does not interfere with theconnection between the outlet 67 of the manifold filter 54 and theconnection line 50. The hinged door 78 also provides a rigid support toa top portion of the manifold filter 54 such that the filter 54 remainsin place when for example, the nozzle 66 couples to the inlet 65 of thefilter 54.

In FIG. 8 , a compartment 76 defines the opening 74 and the opening 74is configured to receive the particular shape and size of the manifoldfilter 54 such that when the manifold filter is inserted downward intothe opening and registered within the compartment 76, at least part ofthe manifold filter 54 is disposed above the platform 22 and at leastanother part of the manifold filter 54 is disposed below the platform 22and in the clean chamber 14. To remove and replace the manifold filter54 between filling phases, an operator need only open the hinged door78, lift the manifold filter 54 out of the opening 74, slide a newmanifold filter 54 into the opening 74, and close the door 78. In someexamples, the opening 74 is sized to receive a cartridge capable ofholding and containing a number of different sized filters.

In FIG. 9 , a second exemplary manifold assembly 122 that may be usedwith the machine 10 of FIGS. 1-3 is constructed in accordance with theteachings of the present disclosure. The second exemplary manifoldassembly 122 is similar to the first exemplary manifold assembly 38, andincludes a plurality of product bags 124, a manifold filter 126, and aconnection line 128 in fluid communication with the product bags 124 andthe manifold filter 126. The second exemplary manifold assembly 122differs from the first exemplary manifold assembly 38 in its connectionto the support wall 18. As shown in FIGS. 1-4 , each product bag 46 ofthe first exemplary manifold assembly 38 is secured to the support wall18 by clamping the spring-force latch 42 at least partially through theaperture 116 of the product bag 46. In the second exemplary manifoldassembly 122 of FIG. 9 , each product bag 124 is pre-assembled to asuspension bar 130 so that each bag 124 is evenly spaced apart to ensurethat each corresponding stem 132 is in vertical alignment (i.e.,perpendicular relative to the connection line 128). An operator needonly align the suspension bar 130 to the support wall 18 and secure thesuspension bar 130 to one or more fasteners or hooks of the machine 10.In this example, the second exemplary manifold assembly 122 obviates theneed to individually clamp each bag 124 to the support wall 18. Each ofthe bags 124, once filled, remains attached to the suspension bar 130 tofacilitate removal of the manifold assembly 122 from the machine 10. Allother features of the second exemplary manifold assembly 122 may be thesame or similar as the first exemplary manifold assembly 38.

Turning to FIG. 33 , a bracket 500 for holding a manifold assembly 38 isconstructed in accordance with the teachings of the present disclosure.The bracket 500 is a wire frame for receiving, storing, and mounting amanifold assembly 38. The bracket 500 defines a plurality of bagcompartments 510, a first hook 512 a and a second hook 512 b, a filtercompartment 514, and a tubing hook 516. The bracket 500 may be loadedwith a manifold assembly 38, as shown in FIG. 34 , and then attached tothe support wall 18 of the machine of FIGS. 1-3 . The bracket 500 mayalso be attached first to the support wall 18, and then the manifoldassembly may be loaded onto the bracket 500. The bracket 500 is arrangedto receive a six-bag manifold assembly 38, however, in other examples,the bracket 500 may be arranged to receive more or fewer product bags46.

In FIGS. 33 and 34 , the bracket 500 includes the first hook 512 a andthe second hook 512 b. As shown, the first hook 512 a and the secondhook 512 b are disposed on first lateral end 518 a and second lateralend 518 b, respectively. Each hook 512 a and 512 b is configured tolatch onto a tab (shown in FIG. 35 ) disposed on the support wall 18 ofthe machine 10 or a rod (shown in FIG. 36 ) of a storage rack. As aresult, the entire bracket and loaded manifold assembly 500 may beeasily transferred from the machine 10 to storage or vice versa.

The bracket 500 defines a plurality of bag compartments 510 for holdingand supporting a plurality of product bags 46. In this example, thebracket 500 defines six adjacent compartments for receiving a manifoldassembly 38 with six or fewer product bags 46. Each compartment 510 issized to receive at least one product bag 46. The product bag 46 issupported at a lower portion of the bag 46 by a first wireframeretaining member 522 and a second wireframe retaining member 524disposed on either side of the compartment 510. The first and secondwireframe retaining members 522 and 524 include a horizontal ledge and avertical wall to retain the product bag 46 in the bladder compartment510. As a result, the product bag 46 is not suspended from the top ofthe bag 46 by a latch or hook.

The bracket 500 also includes the filter compartment 514 on the secondlateral end 518 b of the bracket 500. The filter compartment 514includes a horizontal retaining member 526 and a vertical retainingmember 528. The filter compartment 514 provides easy storage for afilter 54 after each of the bladders 58 have been filled. While thefilter compartment 514 is disposed on the second lateral end 520 b ofthe bracket 500, in another example, the filter compartment 514 may beformed on the first lateral end 520 a.

Additionally, as shown in FIG. 34 , the bracket 500 includes variousslots and hooks for managing tubing of the manifold assembly 38. Forexample, a plurality of two-prong guides 530 are disposed below andbetween the compartments 510 of the bracket 500. When assembling theloaded bracket 500 to the machine 10, the stem 62 of each product bag 46is placed in a slot of the two-prong guide 530. The guides 530 helpalign the stems 62 of the manifold assembly 38 and to avoid any kinks orbends in the tubing, thereby ensuring efficient and accurate filling.Each guide 530 is placed below the port of each stem 62 so that thestems 62 hang straight from the product bags 46.

The bracket 500 also includes one or more tubing hooks 516. The tubinghooks 516 are used to help store the manifold assembly 38 after eachstem 62 is sealed and cut. The tubing hooks 516 support the sealedconnection line 50 with each sealed and cut stem 62. In this way, evenafter the connection line 50, stems 62, and filter 54 are separated fromthe filled product bags 46, all parts of the manifold assembly 38 canremain attached to the bracket 500 until after a filter integrity testis performed on the filter 54. In the illustrated example of FIG. 34 ,the bracket 500 includes two tubing hooks 516 approximately located at amid-point of the product bags 46. However, in other examples the bracket500 may include more or fewer tubing hooks 516. For example, in FIG. 35, the bracket 500 includes three tubing hooks 516 equally spaced along alength of the bracket 500 and closer to the guides 530.

Shown in greater detail in FIG. 35 , the bracket 500 loaded with themanifold assembly 38 is assembled on the machine 10. A tab 550 on thesupport wall 18 receives the first hook 512 a, and on the opposite endof the bracket 500, a second tab receives the second hook 512 b of thebracket 500. Accordingly, an operator may easily and quickly install theloaded bracket 500 on the machine 10 by simply positioning the bracket500 onto the tabs 550 of the support wall 18. When the bracket 500 is inplace on the support wall 18, the guides 530 align with the shelvingunits 136 so that each stem 62 of the manifold assembly 38 is in place.The guides 530 align with the shelving units 136, and may even rest onthe shelving units 136. In this way, the shelving units 136 may supportand distribute the weight of the bracket 500 and loaded manifoldassembly 38 on the machine 10. However, in some cases, the guides 530stop short from engaging the shelving units 136. After the bracket 500is placed on the machine 10, gravity retains the bracket 500 andmanifold assembly 38 on the tabs 550 disposed on the support wall 18 ofthe machine 10.

An operator may load a bracket 500 with a manifold assembly 38 beforethe bracket 500 is placed on the machine 10. In fact, the operator mayload a plurality of brackets 500 with manifold assemblies 38 tostreamline the assembly process. The operator may instead place themanifold assembly 38 onto the bracket 500 after the bracket 500 is hungon the machine 10. After the product bags 46 are disposed in thecompartments 510 and the bracket 500 is disposed on the machine 10, anoperator may load the filter 54 into the filter compartment 76 of themachine 10 to initiate the filling process. The machine 10 can then beoperated to fill each product bag 46.

FIG. 36 illustrates a storage rack 600 for holding and storing aplurality of loaded brackets 500. The storage rack 600 includes a firstrow 602 with a first and second parallel rods 604, 606, and a second row612 with a first and second parallel rods 614, 616. In FIG. 36 , thestorage rack 600 provides short-term storage of the loaded bracket 500after the product bags 46 are filled and sealed, and before the filter54 is tested. Accordingly, the storage rack 600 is designed to supportthe weight of a plurality of loaded brackets 500 on each row.

The first and second rods 604, 606 of the first row 602 are arranged toreceive the hooks 512 a and 512 b of each bracket 500, respectively.Accordingly, the first and second rods 604, 606 are spaced laterallyapart equal to the distance between the first hook 512 a and the secondhook 512 b. The second row 612 is disposed beneath the first row 602 andmay be substantially identical to the first row 602. While the storagerack 602 is shown with a first row 602 and a second row 612, the storagerack 600 may include more or fewer rows than presently shown.

In FIGS. 10 and 11 , an exemplary occlusion valve 134 of the machine 10is illustrated in greater detail and is constructed in accordance withthe teachings of the present disclosure. The occlusion valve 134includes a finger 135 that is movable relative to a stop 150 between theextended position, in which the finger 135 is spaced from the stop 150,and the compressed position, as shown in FIG. 11 , in which the finger135 engages the stop 150. A portion of the stem 62 of each product bag46 is guided between the finger 135 and the stop 150 by a lead-in ramp152 adjacent to the finger 135. The occlusion valve 134 also includes anelectrically energized solenoid 154 that operates the finger 135.

When the occlusion valve 134 is activated, the solenoid 154 isconfigured to move the finger 135 in a direction X to open the occlusionvalve 134 (i.e., to move the occlusion valve 134 to the extendedposition) such that the finger 135 is spaced from the stop 150. In theextended position, the occlusion valve 134 is open to receive a portionof the stem 62 when the manifold assembly 38 is positioned on thesupport wall 18, or when the occlusion valve 134 unclamps the stem 62 ofan attached bag 46 to permit fluid to flow into the bladder 58. Todeactivate or close the occlusion valve 134, the solenoid 154 moves thefinger 135 in a direction Y to close the occlusion valve 134 (i.e., tomove the occlusion valve 134 to the compressed position). When themanifold assembly 38 is coupled to the support wall 18 and the occlusionvalve 134 is deactivated (or in the compressed position), the finger 135compresses the stem 62 of the product bag 46 against the stop 150 suchthat no air and/or fluid may pass through the stem 62 and into thebladder 58. In other examples, simple manual clamps attached to thesupport wall 18 may be provided instead, which may require an operatorto manually clamp and unclamp each stem 62 of the product bag 46 duringthe filling process. The occlusion valve 134 operates in the same orsimilar way when the second exemplary manifold assembly 122 is used.

The solenoid 154 is protected by a housing 156 and is disposed behind afront surface 158 of the support wall 18. The occlusion valve 134 iscommunicatively coupled to the CPU 28 such that an operator may controlthe position of the occlusion valve 134 during attachment of themanifold assembly 38 to the support wall 18. Further, the CPU 28 may beprogrammed to operate each occlusion valve 134 when each correspondingproduct bag 46 is being filled by the filling machine 10.

In FIGS. 12-14 , the sealing and cutting tools are illustrated and willbe described in further detail. Turning first to FIG. 12 , the sealingtool 138 is constructed in accordance with the teachings of the presentdisclosure. The sealing tool 138 has a hand grip 146, a lever 148, and aclamp 160, which is movably coupled to the lever 148 and slidablyconnected to the hand grip 146. The hand grip 146 includes a first end161 that is spaced from the clamp 160 when the sealing tool 138 is in anopen position, as shown in FIG. 12 . To make a seal, the sealing tool138 is movable between the open position and a clamped position, inwhich the first end 161 engages the clamp 160. In particular, the clamp160 includes a sealing bar 162 that engages the first end 161 of thehand grip 146 and a connecting piece 164 that is slidably coupled to thehand grip 146 and secured to the lever 148. The sealing tool 138 emitsradiofrequency (“RF”) energy between the first end 161 and the bar 162(also referenced herein as “opposing clamping surfaces”). RF energyemitted from these opposing clamping surfaces 160, 161 heats up thepolymer stem 62, causing the stem 62 to melt sufficiently to bond andform a seal. The bar 162 of the clamp 160 is shaped to form a wide sealin the stem 62 of the product bag 46 when the bar 162 engages the firstend 161 of the hand grip 146. The sealing tool 138 forms a wide sealhaving a width in a range of approximately 4 mm to approximately 6 mm,and preferably 5 mm. The width of the seal may depend on the propertiesof the tubing of the stem 62, and may be outside this range in order toensure that the seal withstands a squeeze test on the bag for at leastten seconds at 20 psi.

In particular, one or more of the opposing clamping surfaces 160, 161includes one or more electrodes to emit RF energy into the material ofthe stem 62 to seal. RF energy cause the molecules of the material ofthe stem 62 to oscillate in response to the RF field, causing thematerial to heat and melt. For example, one of the clamping surfaces160, 161 is grounded and the other surface is energized by an RF fieldof approximately 27 MHz frequency. In another example, one or more ofthe clamping surfaces 160, 161 may be a heated element.

To operate the sealing tool 138, an operator may grip the hand grip 146and the lever 148 and apply enough pressure to push the lever 148 towardthe hand grip 146 in a V direction. By pushing the lever 148 toward thehand grip 146, the connecting piece 164 of the clamp 160 slides relativeto the hand grip 146 along a longitudinal axis T of the handgrip 148.Specifically, the clamp 160 slides relative to the hand grip 146 whenthe lever 148 rotates in the V direction, and pivots at a pivot point165 where the lever 148 is coupled to the hand grip 146. As the lever148 rotates in the V direction, a first end 166 of the lever 148 pullson the connecting piece 164 of the clamp 160 to move the bar 162 alongthe T axis and closer to the first end 161 of the hand grip 146.

An electrical port 168 is disposed at a second end 170 of the hand grip146. The electrical port 168 is configured to electrically couple to apower source and/or to the CPU 28 so that the CPU 28 of the machine 10can control and/or monitor the usage of the sealing tool 138. Forexample, the sealing tool 138 may include a sensor 185 to monitor theheat applied between the first end 161 of the hand grip 146 and the bar162 of the clamp 160. Additionally, the sealing tool 138 includes atimer 172 to monitor a duration of the sealing tool 138 in the clampedposition.

In one example, the CPU 28 may run an algorithm to determine how longthe RF energy should be applied to the stem 62. For example, when thelever 148 is fully depressed against or toward the hand grip 146, amagnet in the lever 148 trips a switch in the hand grip 146, whichactivates the RF sealing energy between the first end 161 of the handgrip 146 and the bar 162. The RF energy will remain on until a desiredimpedance change between the two sealing surfaces 160, 162 is met,thereby signifying that a proper seal has been made. Once the desiredimpedance change is met, the RF energy is automatically turned off ordeactivated. During this sealing process, the sealing tool 138 sends twosignals to the CPU 28: a first signal that indicates the time that thelever 148 is fully depressed, and a second signal that indicates RFenergy is applied to the stem 62. The CPU 28 receives these signals toprocess how long each signal is active. After the seal is made (i.e.,when the RF energy turns off), the lever 148 remains depressed for twoseconds while the seal cools during a cooling period.

The machine 10 may display a visual indicator to communicate with anoperator for achieving an adequate seal. The visual indicator may bedisplayed on the user interface 26 or may be displayed elsewhere on themachine 10 that is highly visible to the operator, for example, on topof the support wall 18. For example, when the lever 148 is fullydepressed, the first and second signals are sent to the CPU 28, and alight on the machine 10 turns yellow. As long as the lever 148 isdepressed, the first signal communicates with the CPU 28, and the secondsignal communicates RF energy is applied to the stem 62. The CPU 28monitors both signals so that while the RF energy is activated, thelever 148 remains fully depressed. After the RF energy is deactivatedand the second signal stops communicating with the CPU 28, the CPU 28will wait two seconds and the indicator light on the top of the machine10 turns green. If, however, the lever 148 is not fully depressed whileeither the RF energy is on or during the two second cooling period, theCPU 28 will display an error signal on the monitor or flash a red light.Thus, CPU 28 in this example, monitors the time the lever 148 is fullydepressed to ensure enough time for sealing is met, the time the RFenergy is applied to the stem 62, and finally the two-second coolingtime. The green light comes on after additional two seconds to alert theoperator to release the lever 148.

However, in other examples where the sealing process is not automated asdescribed above, the machine 10 may display a pressure gauge ordifferent colored lights, to instruct an operator to apply a certainpressure to the lever 148, to start clamping the stem 62 for certainperiod of time, and/or to release the clamp 160 from the stem 62. Othermethods with additional automation are also possible.

In FIGS. 13 and 14 , a cutting tool 174 is constructed in accordancewith the teachings of the present disclosure. The cutting tool 174includes a hand grip 175, a lever 176, a blade 222 coupled to the handgrip 175, and a stop 224 coupled to the lever 176. While only partiallyillustrated in FIGS. 13 and 14 , the hand grip 175 and the lever 176 ofthe cutting tool 174 are substantially like the sealing tool 138. Thestop 224 includes a blade cover 226 having a groove 228 that receivesthe blade 222 when the cutting tool 174 is in a closed position, and aconnecting piece 230 that is slidably coupled to a first end 232 of thehand grip 175. To make a cut, the cutting tool 174 is movable between anopen position, as shown in FIGS. 13 and 14 , in which the blade 222 isspaced from the blade cover 226 of the stop 224 a distance D, and aclosed position, in which the blade 222 engages the blade cover 226 ofthe stop 224. The lever 176 is spring-operated and pivotably coupled tothe hand grip 175 at a pivot point 234 and secured to the connectingpiece 230 of the stop 224.

To operate the cutting tool 174, an operator may hold the hand grip 175and the lever 176 and apply enough pressure to push the lever 176 in adirection R toward the hand grip 175 until the groove 228 of the bladecover 226 receives the blade 222. When the lever 176 moves in the Rdirection toward the hand grip 175, a spring 238 disposed between thehand grip 175 and the connecting piece 230 of the stop 224 is biased,causing the lever 176 to pull the stop 224 along a longitudinal axis Fof the cutting tool 174 toward the blade 222.

The cutting tool 174 is particularly designed to have a limited opening236 (i.e., the space between the blade 222 and the blade cover 226) toensure that only a sealed portion of the stem 62 can fit within theopening 236. To prevent mistakenly cutting above or below the sealcreated in the stem 62, the opening 236 will not receive any unsealedportion of the stem 62. In one example, the blade cover 226 of the stop224 may be spaced away from the blade 222 a distance D, which is wideenough to accept the thickness of the sealed tube but not wide enough toallow an unsealed tube to fit within the opening 236.

As provided above, the shelving unit 136 of the machine 10 is configuredto align the cutting tool 174 with the seal of the stem 62. The clamp160 of the sealing tool 138 and the stop 224 of the cutting tool 174 areshaped to slide or snap into the notch 144 formed in each shelving unit136 of the machine 10. In this way, the shelving unit 136 guides eachtool 138, 174 to a specific sealing location of the stem 62, between thebladder 58 and the connection line 50, where each bag 46 is to besealed, cut, and separated from the manifold assembly 38.

In FIG. 15 , an exemplary method 200 of the filling process of themachine 10 is illustrated, and will be discussed with reference to FIGS.1-4 . The machine 10 assures production of sterile solution-filledproduct bags 46 by performing a plurality of steps of the method 200.

Initially, a mix tank for containing a solution may be brought into thesame room as the machine 10. A cap removal tool (for removing a capattached to the nozzle 66) is placed onto the machine 10 and extendsdownward into the clean chamber 14. A laminar air source is turned on toprovide air flow through the clean chamber 14. A sterile filter trainmay then be removed from its sterile packaging, and hooked up to themachine 10 connecting the machine 10 to the mix tank. The capped nozzle66 of the filter train is installed in a nozzle holder in the cleanchamber 14, and the feed line 70 connected to the nozzle 66 is threadedout of the clean chamber 14, and the slotted door 82 of the cleanchamber 14 is closed. The installation of the nozzle 66 may be set upfirst because the nozzle 66 must be kept away from contacting othersurfaces during installation as it is downstream from the other elementsof the filter train. The feed line 70 extending from the slotted door 82is then wrapped around the peristaltic pump 102. Finally, a sterileconnector of the filter train is connected to a sterile connector on themix tank and a valve controlling the flow of solution from the mix tankis turned on. In other examples, however, the solution may come from adifferent source coupled to the filter train.

To prepare the machine 10 for filling, an automated process of readyingthe nozzle 66 of the filter train for sterile connection to the manifoldassembly 38 may then be performed. This automated process may include,for example, lowering the nozzle 66 away from the cap removal tool. Thecap removal tool is shaped to hold the cap of the nozzle 66 such that asthe tubing extending from the nozzle 66 is pulled downward and away fromthe cap removal tool, the cap removal tool removes the cap from thenozzle 66. This automated process of removing the cap may be performedonce for each new filter train. However, multiple bag sets 46 may befilled before the filter train needs replacing and decapping. Detailsrelated to this process are described further below.

After this initial setup, the method 200 begins with a step 204 ofpositioning the manifold assembly 38 onto the filling machine 10. Theindividual bags 46 of the manifold assembly 38 are hung with the stems62 threaded through the occlusion valves 134. The manifold assembly 38is suspended such that the stem 62 of each product bag 46 is disposedbelow the bladder 58 of each bag 46 so that a solution is pumped againstthe force of gravity and through the stem 62 to fill the bladder 58 ofeach bag 46. Before filling each product bag 46, the method includes astep 208 of coupling the nozzle 66 to the connection line 50 of themanifold assembly 38 in the clean chamber 14. The nozzle 66 is in fluidcommunication with the batch filter 86 via the feed line 70, and thebatch filter 86 is disposed upstream from the manifold filter 54 suchthat the solution can pass through the batch filter 86 before beingpumped through the nozzle 66 and through the manifold filter 54. Anexemplary step 208 of coupling the nozzle 66 will be described infurther detail below and with reference to FIGS. 16-23 . The machine 10is then activated.

After the nozzle 66 is coupled to the connection line 50 of the manifoldassembly 38, and more particularly, to a portion of the connection line50 in fluid communication with the inlet 65 of the manifold filter 54, astep 212 includes activating the pump 102, which is disposed upstreamfrom the batch filter 86. The pump 102 is configured and controlled toat least partially fill one or more of the bladders 58 associated withthe plurality of bags 46 by pumping solution from the mix bag or othersource of solution through the feed line 70, batch filter 86, the nozzle66, the manifold filter 54, and the connection line 50, thereby creatingone or more at least partially filled product bags 46. In this example,the plurality of occlusion valves 134 are controlled to permit fillingof one bag 46 at a time. The pump 102 may be automated by the machine10, or manually controlled by an operator.

Once the filling process is complete and each of the stems 62 iscompressingly sealed by the associated occlusion valve 134, a step ofsealing 216 the stem 62 of each of the at least partially filled productbags 46 is performed. The stem 62 of each product bag 46 is sealed at alocation between the connection line 50 and the bladder 58 of the atleast partially filled product bags 46, thereby creating one or more atleast partially filled and sealed product bags 46. The sealing step 216may be an automated function performed by the machine 10 or an operatormay make each seal using the sealing tool 138. An exemplary step 216 ofsealing is described in more detail below and with reference to FIGS.24-26 . Finally, each of the at least partially filled and sealedproduct bags 46 is separated, at the seal, from the connection line 50in method step 220, thereby creating a plurality of filled product bags46 that are separated, sealed, and ready for storage and/or shipment.The separation step 220 may be performed automatically by the machine 10or an operator may cut the stem 62 at the seal using the cutting tool174 to separate each bag 46 from the rest of the manifold assembly 38.An exemplary step 220 of separating is described in more detail belowand with reference to FIGS. 24-26 .

The method 200 is performed at least three times to produce a pluralityof viable at least partially filled, sterile, sealed, product bags 46.In a first round of steps 204, 208, 212, 216, 220, the machine 10 andfilter train are primed such that the batch filter 86 is completelywetted to eliminate the chance of receiving a false positive in a filterintegrity test. Additionally, by completely wetting the batch filter 86,any air trapped in the batch filter 86 is transferred to the productbags 46, and particularly, a first product bag 46A (FIG. 4 ). One ormore of the filled bags 46 of the priming phase can be useful forsending to a lab for testing the fluid.

A second round of steps 204, 208, 212, 216, 220 includes attaching asecond manifold assembly 38 to the machine 10 and calibrating themachine 10 to ensure that an equal amount of headspace (e.g., 5 mL) andsolution are filled in each product bag 46. The machine 10 thenindicates to the operator to weigh each filled product bag 46 using thescale 34. The weight of each bag 46 is recorded for tracking and checkedagainst a tolerance factor of the pump 102 to determine the exact amountof solution that will be filled in the final round of filling. Afterweighing all six bags 46, the calibration pump factor is set by the CPU28. During the calibration phase, the occlusion valves 134 are tested toensure that no air passes through the stems 62 when the occlusion valves134 are deactivated.

In the third filling round, the batch filter 86 has been completelywetted, and a third manifold assembly 38 is attached to the machine 10.The third and any subsequent rounds produce viable product bags 46 thatif determined to be sterile, are not discarded like the product bags 46of the priming and calibrating rounds. The third bag set is weighed as aconfirmation of the calibration adjustment performed after the secondbag set. Once the machine 10 is primed and calibrated, the method 200may be repeated until the mix tank is empty or the batch filter 86 meetsits filtration capacity. After each subsequent round, the manifoldfilter 54 of each manifold assembly 38 is tested. Further, a subsequentor additional calibration cycle may be run to recalibrate the machine10.

In each round of the filling process, one bag 46 is filled at a time. Tofill each bag 46 separately, one occlusion valve 134 is activated at atime to move from the collapsed position to the extended position topermit solution to flow into each product bag 46. To fill the first bag46 a, solution from the nozzle 66 is pumped through the manifold filter54 and connection line 50, and pushes air that is trapped in theconnection line 50 into the bladder 58 of the first bag 46 a. When thefirst bag 46 a has a predetermined amount of fluid in the bladder 58,which may be measured by a predetermined number of turns made by theperistaltic pump 102, the method 200 includes deactivating the occlusionvalve 134 associated with the first bag 46 a to move the occlusion valve134 from the extended position to the collapsed position. The machine 10may then automatically activate a second occlusion valve 134 adjacent tothe stem 62 of the second product bag 46 b to move the occlusion valve134 from the collapsed position to the extended position to permit fluidflow into the bladder 58 of the second product bag 46 b. Activating thesecond occlusion valve 134 may simultaneously occur when the firstocclusion valve 134 is deactivated, thus pumping the solution can becontinuous. When the machine 10 is filling the second product bag 46 b,the other occlusion valves 134 are in the collapsed position. In someexamples, the at least partially filled first bag 46 a has a differentheadspace in the bladder 58 than the other product bags 46 because thefirst bag 46 a receives the trapped air in the connection line 50. Assuch, the first bag 46 a may be discarded with the bags 46 of thepriming and calibrating rounds. Alternatively, the first bag 46 a mayinclude a valve that releases the air trapped in the connection line 50such that each of the six product bags 46 are uniform in terms of volumeof solution and headspace.

In one example, the on-board CPU 28 of the machine 10 operates andcontrols the filling process 200 and may interact with an operator bydisplaying commands and status updates via the user interface 26. TheCPU 28 communicates with the pump 102, the connection assembly 90, andthe occlusion valves 134 of the machine 10 to receive information, andcommunicate various commands via the user interface 26 for operating themachine 10. Generally, the CPU 28 is configured to receive signals fromproximity switches, transmit commands or signals to actuating devices,monitor sensors, and process information gathered and received from thesensors. For example, the CPU 28 communicates with the pump 102 to beginpumping a solution and to stop pumping the solution when each of theproduct bags 46 has been filled to a desired capacity. Moreparticularly, in this example, the CPU 28 communicates with eachocclusion valve 134 to permit filling and inhibit filling of eachproduct bag 46 in sequence by activating and deactivating each occlusionvalve 134. The CPU 28 is programmed for each phase of the fillingprocess, and communicates results for the priming and calibration stepsto ensure adequate filling to achieve best results. In the illustratedexample, the CPU 28 controls the operation of the machine 10 locally(e.g., a wired connection) and may be accessed by a control panel of theuser interface 26 located on the support wall 18 of the machine 10. Inother embodiments, the CPU 28 may remotely control the operation of themachine 10 via wireless communication systems.

The CPU 28 may be programmed to store data for each batch of viableproduct bags 46 that have been filled and tested for sterility. Beforefilling, an operator may enter a serial number associated with themanifold assembly 38 into the CPU 28 via the user interface 26 to storetype of solution, solution expiration, filling date and location, fluidconductivity and integrity results, and other information pertainingproduct bags 46. In other examples, each batch of filled product bags 46may be serialized with a barcode, QR code, RFID tag or other identifierto identify critical information related to the filled bag 46 with orwithout the use of the CPU 28. For example, each bag 46 may haveinformation relating to the filling of that bag 46 such as, for example,the machine 10 used to fill the product bag 46, the time and date offilling, and other data associated with the contents of the bag 46. Thisidentifier can help track the shipment and distribution of each bag 46.For example, in the case that the contents of the bag 46 is containscontamination, the other bags 46 produced in that same batch can belocated and/or discarded. In one example, if a filter 54 of the bag setfails, then each of the corresponding bags 46 may be segregated out fordiscard. This tracking could also help identify any problems in themachine 10. The label or identifier may be placed on the outside surfaceof the bladder 58, sealed border 112, stub of the access ports 108, orother part of the bag 46. The bags 46 may be labeled before or after thebags 46 are filled.

To ensure sterility of the contents of the product bag 46, the manifoldfilter 54 is sealed off and separated from the connection line 50 fortesting in a filter integrity test machine. In particular, thedownstream or outlet tube from the filter 54 is trimmed. The tube istrimmed such that it is long enough so the outlet end can be placed in areceptacle to catch any drips during the test. Each filter 54 may betested individually, or three filters 54 are tested simultaneously. Forexample, three leads from the filter testing device are connected to theinlet of each of three filters 54. If there is a failure then each ofthe three filters 54 is individually tested.

The filter testing device may be pre-programmed or controlled to performa filter integrity test, such as a bubble point test, a pressuredegradation test, water intrusion test, a water flow test, or anysuitable test known in the art. A pressure degradation test is a methodfor testing the quality of a filter either before or after the filterhas been used. To perform the integrity test, a test head of the filtertesting device engages the inlet 65 of the manifold filter 54. Thefilter integrity test determines the presence of any structural flaws inthe filter membrane that may prevent the filter 54 from adequatelysterilizing a fluid. For example, a hole having a diameter larger than0.2 microns (μm) in the filter membrane may allow particulates in thefluid to pass through the filter 54 and compromise or contaminate thesterile environment of the bladder 58.

To perform the filter integrity test using a pressure degradation testprocedure, the test head engages the inlet 65 of the filter 54 andapplies an air pressure of a predetermined value to the inlet 65 andfilter membrane. In one example, the predetermined value is the pressurewhere gas cannot permeate the membrane of an acceptable filter. Apressure sensor, or other method of measuring the integrity of thefilter, is located within the test head and measures the pressure decayor diffusion rate through the filter membrane. The results from theintegrity test are assessed to determine the quality of the filter 54,and therefore the quality of the solution of the filled product bags 46.If the pressure sensor measures a decay or an unexpected rate of decay,then the filter 54 fails the test.

Alternatively in a bubble point test, the test head gradually increasesthe pressure applied to the filter 54, and the increase in pressure ismeasured in parallel with the diffusion rate of the gas through thefilter media. Any disproportionate increase in diffusion rate inrelation to the applied pressure may indicate a hole or other structuralflaw in the filter membrane, and the filter 54 would fail the integritytest.

Based on the results of the filter integrity test, a determination thatthe solution of the filled product bag 46 is either sterile or has thepotential of being compromised may be made with a high degree ofcertainty. The filter integrity test performed in a filter integritytest machine is not limited to those methods described herein, and mayinclude a different acceptable filter test designed to assess thequality and performance of the filter 54.

Turning now to FIGS. 16-23 , the step 208 of coupling the nozzle 66 tothe connection line 50 of the manifold assembly 38 of the method 200 ofFIG. 15 will now be described in further detail. The step 208 includes aplurality of intermediate steps before the pump 102 is activated tobegin pumping. Exemplary performance of these intermediate steps areillustrated in FIGS. 16-23 , and include a nozzle de-capping phase(FIGS. 16 and 17 ), a manifold filter insertion phase (FIG. 18 ), aremoving a sealed end phase (FIGS. 19-21 ), and finally the nozzlecoupling phase (FIGS. 22 and 23 ).

Turning first to FIG. 16 , the connection assembly 90 is disposed in theclean chamber 14 and includes the nozzle holder 92 movable by a firstactuator 178, the cutting tool 94 movable by a second actuator 179, andthe line grip 98 movable by a third actuator 180. Each actuator 178,179, 180 may be automatically activated to complete the step 208 ofcoupling the nozzle 66 to the connection line 50 by the CPU 28. In otherexamples, the actuators 178, 179, 180 may be activated manually by anoperator.

In FIGS. 16 and 17 , the connection assembly 90 is depicted in aninitial de-capping phase. In this phase, the nozzle 66 is coupled to thenozzle holder 92 and the first actuator 178 is in an extended position,and each of the second and third actuators 179, 180 is in a retractedposition. A cap removal tool 182 is removably disposed within thecompartment 76 formed in the platform 22 and extends into the cleanchamber 14. The cap removal tool 182 may be inserted into a receivingmember of the compartment 76 in the chamber 14 so that the cap removaltool 182 can be inserted and removed easily from the chamber 14. Oncethe cap removal tool 182 is in place, an operator may insert a cap 184of the nozzle 66 into a first opening 186 formed in the cap removal tool182. The first opening 186 is perpendicular to a longitudinal A axis ofthe nozzle holder 92 and is sized to receive the cap 142 of the nozzle66. Once in place, the cap 184 sits against a flange defined by capremoval tool 182 in a vertical or upright position. Once the nozzle 66is secured to the cap removal tool 182 via the nozzle cap 184, theoperator closes the door of the compartment and laminar air flowsthrough the chamber 14.

The cap removal tool 182 also includes a second opening 187 disposedorthogonally relative to the first opening 186 and is sized to slidablyreceive the nozzle 66. The second opening 187 formed in a bottom side ofthe cap removal tool 182 is sized to permit movement of the nozzle 66away from the cap removal tool 182, but is too narrow to permit the cap184 to slide with the nozzle 66.

To remove the cap 184 from the nozzle 66, the first actuator 178 movesfrom the extended position to a retracted position, carrying the nozzleholder 92 and the nozzle 66 downward in a L direction. As the nozzleholder 92 and nozzle 66 move downward, the nozzle 66 slides through thesecond opening 187 of the cap removal tool 182, and the cap 184 isremoved from the nozzle 66 and remains, temporarily, in the cap removaltool 182. In particular, the second opening 187 is too narrow to permitthe cap 184 from moving with the nozzle 66 in the L direction. A flangeof the cap removal tool 182, which defines the second opening 187,engages a lower edge of the cap 184 as the nozzle holder 92 movesdownward. The cap removal tool 182 thereby retains the cap 184 in theopening of the cap removal tool 182 and separates the cap 184 from thenozzle 66. The cap 184, now removed from the nozzle 66, is retained inthe cap removal tool 182 until the cap is removed when the cap removaltool is removed from the machine 10. This automated process prevents anoperator from needing to form any touching contact with the nozzle 66once the nozzle 66 is placed in the clean chamber 14. In this way, theclean environment of the nozzle 66 and/or the chamber 14 is notcompromised and the inlet 65 of the manifold filter 54 makes aconnection with the nozzle 66 during this step within the sterileenvironment of the clean chamber 14.

After the cap 184 is removed, the cap removal tool 182 may be removedfrom the compartment 76 and replaced with the manifold filter 54, asshown in FIG. 18 . During the manifold filter insertion phase, thefirst, second, and third actuators 178, 179, 180 are in the retractedpositions. An operator opens the protective door 78 and slides themanifold filter 54 into the compartment 76 defined by the opening 74 inthe platform 22, as shown in FIG. 6 . Once the manifold filter 54 ispartially extending above the platform 22 and partially extending intothe clean chamber 14, the manifold filter 54 is in place, and theprotective door 78 is closed, as shown in FIG. 7 . The compartment 76 isparticularly configured to align the inlet 65 of the manifold filter 54with the longitudinal A axis of the nozzle 66.

The step 208 of coupling the nozzle 66 to the connection line 50 of themanifold assembly 38 more specifically includes coupling the nozzle 66to the manifold filter 54. As shown in FIG. 18 , the manifold filter 54includes a connection tube 188 connected to the inlet 65 of the filter54. In an embodiment, the connection tube is formed as a flexible,polymeric tubing segment having an outlet end section bonded to a rigidinlet port of the filter housing 54. The connection tube 188 has asealed end 190 that is opened before the nozzle 66 connects to the inlet65 of the filter 54 to fluidly couple the nozzle 66 to the connectionline 50 of the manifold assembly 38. From the perspective of FIG. 18 ,the sealed end 190 is disposed between the nozzle 66 and the inlet 65 ofthe manifold filter 54. Opening the sealed end 190 includes cutting theconnection tube 188 at a location between the sealed end 190 and thefilter inlet 65, thereby creating an inlet to the connection tube 188,an opening, and fluid connection to the manifold assembly 38. The sealedend 190 may be integrally formed with the connection tube 188 by sealingan end section of the tube 188 together using, for example, RF or heatsealing. However, in other examples, the sealed end 190 may be sealedshut by a sealing cap or other piece bonded to the end of the connectiontube 188. In this case, opening the sealed end 190 may include removinga sealing cap or other component from the connection tube 188.

In FIG. 19 , opening the sealed end 190 includes holding the connectiontube 188 via the line grip 98 and moving the cutting tool 94 toward theconnection tube 188 to cut off the sealed end 190 (as shown in FIG. 20 )at a location between the sealed end and the inlet port of the filterhousing 54. The line grip 98 engages the connection tube 188 when theline grip 98 is in the extended position. Specifically, a protruding tab192 of the line grip 98 has an opening sized to receive thecircumference of the connection tube 188 and hold the connection tube188 in vertical alignment. The line grip 98 facilitates the opening ofthe sealed end 190 by holding the connection tube 188 in place while thecutting tool 94 removes the sealed end 190 of the connection tube 188.The third actuator 180 carries the line grip 98 to move in a directionM, relative to a B axis, to engage the connection tube 188. In otherexamples, the line grip 98 may not be needed for opening the connectiontube 188.

The cutting tool 94 includes a blade 194 and an angled chute 195disposed below the blade 194. The cutting tool 94 is movable by thesecond actuator 179 between the retracted position, as shown in FIG. 19, and an extended position, as shown in FIGS. 20 and 21 . The secondactuator 179 moves in a direction P, relative to a C axis, which isperpendicular to the longitudinal A axis of the nozzle 66 and parallelto the B axis. As shown in FIGS. 20 and 21 , opening the sealed end 190includes holding the connection tube 188 via the line grip 98 and movingthe cutting tool 94, via the second actuator 179, along the C axistoward the connection tube 188. The blade 194 is sharp to pierce theconnection tube 188 and sever the sealed end 190 from the remainder ofthe connection tube 188. More clearly shown in FIG. 21 , the grippingtool 98 includes a slot 196 sized to receive the blade 194 of thecutting tool 94 when the second actuator 179 is in the extended positionand the third actuator 180 is in the extended position. The severedsealed end 190 falls into the angled chute 195 and is discarded.

In FIGS. 22 and 23 , the final phase of coupling the nozzle 66 to theconnection line 50 of the manifold assembly 38 includes directlycoupling the nozzle 66 with an open end of the of connection tube 188.To couple the nozzle 66 with the connection tube 188, the first actuator178 moves the nozzle 66 along the longitudinal A axis of the nozzle 66.As the nozzle 66 moves from the retracted position to the extendedposition, a tapered tip 197 (FIG. 21 , which may have a chamfered end)of the nozzle 66 slides into the open end (hidden from view) of theconnection tube 188 to sealably couple the nozzle 66 to the manifoldfilter 54. The inlet end of the now cut connection tube 188 envelopesthe tip 197 of the nozzle 66, thereby creating a seal by an elastomerichoop stress around the nozzle 66. In other words, the cut connectiontube 188 stretches around the chamfered end 197 to connect with thenozzle 66, thereby creating a seal between an interior wall of theconnection tube 188 and an outer surface of the nozzle 66. At or aroundthe same time, a portion of the connection tube 188 immediately adjacenta rigid end of the inlet port of the filter housing 54 is pinchedbetween the nozzle tip 197 and the rigid end. Together, the hoop stressseal and the pinching seal may provide an additional measure to keep theconnection from leaking because a high degree of back pressure will becaused by flowing the fluid through the filter immediately downstream ofthe connection at the desired flow rate for filling the product bags 46.Once this connection is made, the pump 102 may start pumping solutionthrough the feed line 70, nozzle 66, connection tube 188, manifoldfilter 54, and into the connection line 50 of the manifold assembly 38to fill the product bags 46. The product bags 46 are filled one at atime and sequentially.

To disconnect the nozzle 66 from the manifold filter 54, the pump 102 isreversed, drawing solution disposed in the connection line 50 away fromthe nozzle 66. By reversing the pump, a negative pressure in theconnection line 50 is created, causing the connection line 50 topartially collapse. Thus, when the nozzle 66 is moved in the L directionto decouple the nozzle 66 from the connection line 50, the connectionline 50 recovers so that the solution is drawn away from the interfacebetween the connection line 50 and the nozzle 66 to prevent the solutionfrom spilling onto the nozzle 66 or other equipment in the clean chamber14.

By providing a sterile connecting enclosure within the filling machine10, the distance of the downstream tubing to the filter and manifold 38is minimized, thereby reducing product loss in that tubing and alsofacilitating set up.

Turning now to FIGS. 24-26 , an example of the step 216 of sealing thestem 62 of the product bag 46 of the method 200 is more clearlyillustrated. The step 216 includes aligning the sealing tool 138 at thelocation between the connection line 50 and each bladder 58 of the atleast partially filled product bags 46. In the illustrated example, theshelving unit 136 facilitates this alignment by guiding the sealing tool138 to the location of sealing. As shown in FIGS. 25 and 26 , the handgrip 146 of the sealing tool 138 rests against the platform 140 of theshelving unit 136, and the first end 161 of the hand grip 146 and theclamp 160) are positioned in the notch 144 formed in the stem grip 142.As shown in FIG. 25 , the stem grip 142 includes a groove 229 thatreceives the stem 62 of the product bag 46. The notch 144 isperpendicular relative to the groove 229 and has a profile 231 shaped toreceive the first end 161 of the hand grip 146 and at least a portion ofthe clamp 160.

As shown in FIG. 26 , the stem 62 is disposed between the bar 162 of theclamp 160 and the first end 161 of the hand grip 146 when the sealingtool 138 is in the open position. Once the sealing tool 138 is coupledto the shelving unit 136 and aligned with the stem 62, the step ofsealing 216 the stem 62 includes creating a wide seal by applying RFenergy to the location of the stem 62 by pressing the first end 161 ofthe hand grip 146 toward the bar 162 of the clamp 160, thereby clampingand sealing the stem 62 from the connection line 50. The sealing tool138 is configured to create seal having a width W in a range ofapproximately 4 mm to approximately 6 mm, and preferably 5 mm. To ensurean adequate seal, the step 216 of sealing the stem 62 includes clampingthe stem 62 of each at least partially filled product bags 46 for atleast until a desired impedance change between the two sealing surfaces160, 161 is met.

In some examples, the sealing tool 138 may be communicatively coupled tothe CPU 28 to guide an operator, step by step, to create an adequateseal. For example, the sensor 185 of the sealing tool 138 measures RFenergy applied between the opposing clamping surfaces 160, 161, and thetimer 172 measures the time the sealing tool 138 is in the clampedposition and/or the time RF energy is applied between the opposingclamping surfaces 160, 161. The CPU 28 may be programmed to determine anadequacy of the seal by receiving real-time measurements from the sensor185 and the timer 172. Specifically, the CPU 28 may monitor the RFgenerating circuit (e.g., an LCR circuit) to ensure that a forward andreflected power delivered into the stem 62 to create the seal meetsestablished process requirements. By comparing the measurements receivedfrom the sensor 185 and the timer 172 against a sealing threshold (i.e.,impedance change) and a time threshold, respectively, the CPU 28 candetermine whether the sealing step 216 is satisfactorily performed. Ifpressure is applied beyond of this range or above/below a certainimpedance threshold, the CPU 28 may activate an alarm indicating that aninadequate seal was formed in the stem 62. The seal may also bedetermined inadequate when the operator fails to fully depress the lever148 while the RF energy is activated and remains depressed during thetwo second cooling period. In another example, a message may bedisplayed on the user interface 26 when the time of sealing has reachedthe predetermined threshold and may alert the operator to release thesealing tool 138, or the CPU 28 may automatically cut off power to theend 160 or force the sealing tool 138 to release. In other examples, theCPU 28 may monitor the physical properties of the seal, and inparticular, whether a width of the seal results in a range ofapproximately 4 mm to approximately 5 mm.

In FIGS. 27-29 , the step 220 of separating the product bag 46 is shownin an illustrated example. The step 220 includes waiting until the sealis cooled and aligning the cutting tool 174 at the stem location betweenthe connection line 50 and each bladder 58 of the at least partiallyfilled product bags 46. In this position, the blade 222 of the cuttingtool 174 is aligned with a center point of the wide seal formed in thestem 62 of each of the at least partially filled and sealed product bags46. In the illustrated example, the shelving unit 136 facilitates thisalignment by guiding the cutting tool 174 to the location of sealing. Asshown in FIGS. 27 and 28 , the hand grip 175 of the cutting tool 174 isresting against the platform 140 of the shelving unit 136 and the firstend 232 of the hand grip 175 and the stop 224 are positioned in thenotch 144 formed in the stem grip 142.

As shown in FIG. 29 , a seal 240 in the stem 62 is disposed between theblade cover 226 of the stop 224 and the blade 222 secured to the firstend 232 of the hand grip 175 when the cutting tool 174 is in the openposition. Once the cutting tool 174 is coupled to the shelving unit 136and aligned with the seal 240 of the stem 62, as shown in FIGS. 27-29 ,the step of separating 220 the stem 62 at the seal 240 includes cuttingthe stem 62 of each at least partially filled and sealed product bags 46at the location between the connection line 50 and the bladders 58. Thestem 62 is cut by pressing the blade 222 toward the blade cover 226,thereby piercing and severing the stem 62 from the connection line 50 atthe seal 240. Due to the width of the wide seal 240, the stem 62 issealed at a first side 242 and a second side 244 of the cut. As such,because both resulting first and second sides 242, 244 of the tubing issealed after the stem 62 is cut, an operator can transport the manifold38, bags 46, and filter 54 without any dripping any fluid remaining inthe tubing.

The method steps of sealing 216 and separating 220 the stem 62 from theconnection line 50 may occur simultaneously with the filling of the bags46. For example, the step 212 of at least partially filling one or moreof the bladders 58 associated with the plurality of bags 46 includesfilling the first bag 46 a before filling the second bag 46 b. Anoperator may seal the stem 62 associated with the first bag 46 a andseparate the first bag 46 a from the connection line 50 while the secondbag 46 b is being at least partially filled with solution. Similarly, asthe third bag 46 c is being at least partially filled with solution, theoperator may seal the stem 62 associated with the second bag 46 b andseparate the second bag 46 b from the connection line 50. However, inanother example, the operator may wait until each bag 46 a, 46 b, 46 c,46 d, 46 e, 46 f is filled before performing the sealing 216 andseparating steps 220.

While the illustrated examples includes sealing the stem 62 with thesealing tool 138 using RF energy and then cutting the stem 62 at theseal with the cutting tool 174, other methods of sealing and separatingthe stem 62 may be possible. In one example, the step 216 of sealing thestem 62 includes creating a hot notched seal that creates a weakcenterline in the seal so that the step 220 of separating each of the atleast partially filled and sealed product bags 46 includes pulling thestem 62 to tear at the hot notched seal without using the cutting tool174. In other examples, the sealing and cutting tool may be anintegrated device. For example, an integrated tool may include one handgrip and two separate handles (i.e., one handle for clamping to create aseal and another handle for clamping to cut the seal). In anotherexample, the element 160 may add direct heat to the stem 62 such thatthe passageway is sealed. In another example, the element 160 may beremovably coupled to the first end of the hand grip 146 and may bereplaced with the blade 222 when a seal needs to be cut.

To ensure sterility of the contents of the product bag 46, the manifoldfilter 54 is sealed off and separated from the connection line 50 fortesting in a filter integrity test machine. The operator may repeatsealing and separating methods used to separate each bag 46 from theconnection line 50 to separate the manifold filter 54 from theconnection line 50. In particular, a wide seal may be created at asecond location adjacent to the outlet 67 of the filter 54, and thenseparated such that the connection line 50 and the manifold filter 54are completely sealed off. Thus, a final step in the method 200 is totest the manifold filter 54 using a filter integrity testing device ormachine. The results from the integrity test are assessed to determinethe quality of the filter 54, and therefore the quality of the solutionof the filled product bags 46. If the pressure sensor measures a decayor an unexpected rate of decay, then the filter 54 fails the test.

The machine 10 described herein may be part of a system of machines,such as a first exemplary filling system 250 illustrated in FIG. 30 . InFIG. 30 , the filling system 250 includes three filling machines 254,258, 262, each machine in fluid connection with a mix tank 266, whichprovides the solution for filling the product bags attached to eachmachine 254, 258, 262. In the illustrated example, the mix tank 266includes one port and a four-way valve connected to the port to fluidlyconnect the mix tank 266 to each filling machine 254, 258, 262. However,in another example, the mix tank 266 may include three ports where oneach port, a valve connects the port to a connector that makes a sterileconnection to a complementary sterile connector on the filter trainconnected to the filling machine 254, 258, 262. Other configurations forfluidly coupling the mix tank 266 to each filling machine 254, 258, 262are possible, and the number of ports may reflect the number of fillingmachines in the system. Adjacent to each filling machine 254, 258, 262is a filter integrity test machine 270, 274, 278, respectively. In thislayout, three operators may work simultaneously at each machine 254,258, 262. Alternatively, one operator may operate all three machines254, 258, 262 at different stages of the filling process.

FIG. 31 illustrates a second exemplary filling system 300 assembled inaccordance with the teachings of the present disclosure. In this system300, one operator has access to six different filling machines 304, 308,312, 316, 320, 324. The system 300 includes two mix tanks 328, 332 tosupply solution to the six filling machines 304, 308, 312, 316, 320,324. In this system, one filter integrity test machine 336 is provided.According to this layout, an operator has 360 degrees of visibility ofthe mix tanks 328, 332 and the filling machines 304, 308, 312, 316, 320,324 so that the operator can move easily between mixing and fillingstations of the system 300. In the illustrated example, each mix tank328, 332 includes one port and a four-way valve connected to the port tofluidly connect the mix tank 328, 332 to each filling machine 304, 308,312 and 316, 320, 324, respectively. However, in another example, eachmix tank 328, 332 may include three ports where on each port, a valveconnects the port to a connector that makes a sterile connection to acomplementary sterile connector on the filter train connected to eachfilling machine 304, 308, 312, 316, 320, 324. Other configurations forfluidly coupling the mix tanks 328, 332 to each filling machine 304,308, 312, 316, 320, 324 are possible, and the number of ports mayreflect the number of filling machines in the system.

Finally, FIG. 32 illustrates a third exemplary filling system 350assembled in accordance with the teachings of the present disclosure. Inthis system 350, one filling machine 354 is connected to two differentmix tanks 358, 362 via a connection line 366. A three-way valve 370 iscoupled to the mix tanks 358, 362 and the connection line 366 to controlflow of solution from the mix tanks 358, 362 to the filling machine 354.This system 350 may save time in the filling process because one mixtank 358, 362 may be mixing a solution while the other mix tank 358, 362may be dispensing a pre-mixed solution to the machine 354. As such, themachine 354 may be utilized when one of the mix tanks 358, 362 ispreparing the solution, thereby reducing effects of mix tank down timefor mixing the solution.

The filling machine, mix tank, and filter integrity test machine aremodular, allowing an operator to create any number of different systemconfigurations to best suit the facility's capabilities or customerdemand. Each filling machine, mix tank, and filter integrity testmachine may be placed on a wheeled base so that each station of thefilling process can be mobile.

The method 200, systems 250, 300, 350, and machine 10 disclosed hereinprovide considerable benefits over current methods of terminalsterilization. The machine 10 is portable and self-containing, allowingcustomization of a filling system to meet a particular facility'sspecifications or a market demand. Additionally, the method 200described herein provides sterile solution bags 46 without using asterilizing autoclave and/or expensive sterilization equipment requiredto sterilize the working environment and eliminates the risk offormulation degradation due to heat exposure. The self-contained andautomated machine 10 reduces the sterilization procedures necessary tobe performed in terminal sterilization processes.

The method 200 and machine 10 disclosed herein also reduce risk ofcontamination. The product bag 46 having a filter 54 disposed in-linewith a stem 62 avoids exposing the post-filtered sterile fluid to theenvironment. Rather, the solution, that has passed through thesterilizing manifold filter, is never exposed to the environment beforeflowing into the product bag 46 thereby producing a product bag filledwith fluid that has been subject to terminal sterilization filtration.Moreover, the stem 62 is sealed and cut after filling such that noenvironmental exposure of the fluid can take place. In the case asterilizing filter 54 is determined to be compromised, the bag 46 orbags 46 containing fluid from that filter would be contained anddiscarded without contaminating the processing equipment of the machineor other product bags being processed.

Additionally, the connection assembly 90 takes place entirely in a cleanair space with an upside down configuration of the manifold assembly 38.The inlet of each product bag faces downward such that any drips fromthe cut stems of the product bags 46 will fall onto the platform 22 orclean chamber 14 rather than dripping onto the outer surface of theproduct bags 46. The upside-down configuration also facilitates airmanagement by advantageously using the buoyancy of the air to push thesolution (coming in from below the air, or headspace, of the bag) toensure accurate filling volumes. Because the pump 102 works againstgravity, bubbles that are usually produced during filling are minimized,leading to uniform distribution of headspace and solution in each bag 46of a bag set. Also, by filling from the bottom, for each bag 46 all airin the inlet stem and within the initial empty bag 46 is captured in theheadspace so that each bag 46 ends up with generally the same volume ofheadspace. In other words, the air bubbles pushed out of the fluidpassageways at least partially rely on the buoyancy of the air to createthe headspace. This prevents some bags 46 from visually appearing ashaving different volumes than others simply because the headspace volumeis different.

Disposing the manifold filter 54 in an upside-down configuration alsoprovides advantages in terms of filter integrity test results. The inlet65 of the manifold filter 54 faces down so that the interior of thehousing is completely filled with solution as the manifold tubing isprimed thus the filter 64 is completely wetted before solution flowsthrough the outlet 67 of the filter 54. By ensuring that the manifoldfilter 54 is completely wetted prior to the filter integrity testing,integrity test results are more accurate and minimize false positivetest results.

FIGS. 37A and 37B illustrate a filter integrity test system 650 used fortesting multiple filters 54 at once. As shown, the filter test system650 includes a computer 652 and a connected filter testing apparatus654. In some cases, the computer 652 and filter testing apparatus 654are integral components of a single machine. Additionally, as shown, thefilter testing apparatus 654 is configured to test up to three filtersat one time. However, in some cases, the filter testing apparatus 654may be arranged to test more or fewer filters at once.

The computer 652 controls the filter testing apparatus 654 and alsoreceives and processes information generated by the filter testingapparatus 654. As shown, the computer 652 includes a display 662 andexternal input devices such as a keyboard 664 and a barcode scanner 666.In some examples, the display 662 is also an external input device andcan receive user inputs via a touch-screen interface. During operation,a lab technician can scan barcodes disposed on the filter, whichcorrelate with the barcodes on the product bags, and input data via thekeyboard 664. The computer 652 may additionally include access to aremote computer system, including the internet. In such a case, thecomputer 652 can transmit data, including the filterbarcode/identification and whether the filter 54 passed the filter test.

The filter testing apparatus 654, as shown, tests filters via a standardbubble point test. Accordingly, the filter testing apparatus includes aslot 670 to receive a filter 54. In some cases, the filter testingapparatus 654 includes a connection for both the filter inlet andoutlet. As illustrated, the filter testing apparatus 654 includes theconnection 674 attached to an actuating lever 678. The connection 674may further include a valve, such as a one-way valve. As shown in FIG.37B, the filters 54 are disposed in the slots 670 and the levers 678 areactuated causing the connections 674 to fluidly couple with the filters54. Depending on the filter testing apparatus 654, the connection 674may fluidly couple with the filter inlet 65 or the filter outlet 67. Asa result, the filter testing apparatus 654 can test the filters 54 bypassing pressurized air through each filter 54. In some examples, thecomputer 652 and filter testing apparatus 654 test each filter 54consecutively, but it is possible for all filters to be testedsimultaneously. When a filter 54 passes the filter test, the filledbladders 58 are considered to have been filled in a sterile manner.After the filter test, the filters 54 may be returned to theirrespective filter compartment 514 of the bracket 500 or may bediscarded.

The figures and description provided herein depict and describepreferred embodiments of filling machine, method, and system forpurposes of illustration only. One skilled in the art will readilyrecognize from the foregoing discussion that alternative embodiments ofthe components illustrated herein may be employed without departing fromthe principles described herein. Thus, upon reading this disclosure,those of skill in the art will appreciate still additional alternativestructural and functional designs for the filling machine, method, andsystem. Thus, while particular embodiments and applications have beenillustrated and described, it is to be understood that the disclosedembodiments are not limited to the precise construction and componentsdisclosed herein. Various modifications, changes and variations, whichwill be apparent to those skilled in the art, may be made in thearrangement, operation and details of the methods and componentsdisclosed herein without departing from the spirit and scope defined inthe appended claims.

What is claimed:
 1. A method for producing sterile solution productbags, the method comprising: positioning a manifold assembly onto afilling machine, the manifold assembly including a plurality of bags, afilter, and a connection line in fluid communication with the filter,wherein each of the plurality of bags includes a bladder and a stemhaving a first end in fluid communication with the bladder and a secondend in fluid communication with the connection line; at least partiallyfilling one or more of the bladders associated with the plurality ofbags by pumping fluid through the filter and the connection line,thereby creating one or more partially filled product bags; sealing thestem of each of the at least partially filled product bags at a locationbetween the connection line and the bladder of the at least partiallyfilled product bags, thereby creating one or more at least partiallyfilled and sealed product bags having a seal; separating, at the seal,each of the at least partially filled and sealed product bags from theconnection line; determining an adequacy of the seal in which the sealis inadequate when at least one of (a) and (b) is detected: (a) failingto meet a sealing time threshold, and (b) releasing a sealing tool whena melting point of the stem is reached such that the passageway issealed; and activating an alarm when an inadequate seal is formed in thestem.
 2. The method of claim 1, further comprising aligning a sealingtool at the location between the connection line and each bladder of theat least partially filled product bags.
 3. The method of claim 2,wherein aligning the sealing tool includes inserting the sealing toolwith a registration position adjacent to the stem one of the pluralityof bags, the filling machine including a registration position for eachof the plurality of bags.
 4. The method of claim 3, further comprisingaligning a cutting tool at the location between the connection line andeach bladder of the at least partially filled product bags such that ablade of the cutting tool is aligned with a center point of the sealformed in the stem of each of the at least partially filled and sealedproduct bags from the connection line.
 5. The method of claim 4, whereinaligning the cutting tool includes inserting the cutting tool into theregistration position.
 6. The method of claim 1, wherein separatingincludes cutting the stem of each at least partially filled and sealedproduct bags at the location between the connection line and thebladders, thereby creating a cut in the stem such that the stem issealed at a first side and a second side of the cut.
 7. The method ofclaim 1, further comprising displaying a first identifier to beginsealing and displaying a second identifier to stop sealing.
 8. Themethod of claim 1, further comprising performing a filter integrity teston the filter after separating the filter from the manifold assembly. 9.The method of claim 1, wherein at least partially filling one or more ofthe bladders associated with the plurality of bags includes filling afirst bag before filling a second bag.
 10. The method of claim 9,wherein sealing the stem of each at least partially filled product bagsincludes sealing a stem associated with the first bag while the secondbag is being at least partially filled with fluid.
 11. The method ofclaim 1, wherein positioning the manifold assembly includes attaching arack holding the manifold assembly to the support wall of the fillingmachine, the rack including a plurality of compartments for holding theplurality of bags of the manifold assembly.